1. Field of the Invention
The present invention in general relates to calebinoids. More specifically, the present invention relates to a simple, economical and scalable green process for the synthesis of Calebin A and its biologically active analogs.
2. Description of Prior Art
Darrick S. H. L. Kim and So-Young Park isolated and identified Calebin-A from Curcuma longa in 2001 (Park S. Y. & Kim, D. S. H. L., J. Nat. Prod., 2002, 65, 1227-1231). Demethoxycalebin-Al and demethoxycalebin-A2 have been isolated as a pair from Curcuma longa by Feng Qiu et al. in 2007 (Zeng, Y. C., Qiu, F., Takahashi, K., Liang, J. M., Qu, G. X. & Yao, X. S., Chem. Pharm. Bull., 2007, 55, 940-943). By analogy, bisdemethoxycalebin-A may also be present in Curcuma longa though not reported yet. Darrick S. H. L. Kim and Jin Y. Kim synthesized Calebin-A and some of its analogs through a circuitous route (five steps) starting from 1-hydroxyacetone (1) (Kim, D. S. H. L. & Kim, J. Y., Bioorg. Med. Chem. Lett., 2001, 11, 2541-2543). The calebinoids having free p-hydroxy group are biologically active. Subsequently D. H. S. L. Kim has patented the pharmaceutical compositions of Calebin-A and its analogs as useful for prevention and treatment of β-amyloid peptide-induced disease [U.S. Pat. No. 7,572,829 B2 (2009). This synthesis has been represented as FIGURE-Prior Art. In short, this prior art synthetic scheme involves protection of 1-hydroxyacetone (1) and vanillin (4) as their tetrahydropyranyl (THP) ethers (2 & 5) using dihydropyran. THP ether of 1-hydroxyacetone (2) is treated with Lithium diisopropylamide (LDA) at low temperature (−78° C.) to generate the lithio anion at the α-methyl of the keto group. This lithio anion adds to the aldehyde group of the THP ether of vanillin (5) to give the β-hydroxy-ketone (3). This is dehydrated and deprotected to Feruloylmethanol (6) which is coupled to ferulic acid (7) in the presence of 4-dimethylaminopyridine (DMAP), DMAP-HCl and N,N-Dicyclohexylcarbodiimide (DCC) to get Calebin-A (10a). The synthetic scheme for Calebin-A discussed herein above is the only known for Calebin-A and its analogs. However, it suffers from the following technical disadvantages.                1. The starting material 1-hydroxyacetone is expensive.        2. The condensation of vanillin with 1-hydroxyacetone involves protection of the hydroxyls as their THP ethers to avoid Lithium diisopropylamide reacting with hydroxyls.        3. 4-dimethylaminopyridine and N, N-Dicyclohexyl carbodiimide are also expensive.        4. The synthesis involves a minimum of five steps, very low temperature (−78° C.), pyrophoric and moisture sensitive reagents.        
All aforesaid factors make this process industrially non-feasible for scale up.
It is therefore the principle objective of the present invention to describe a simple, economical, scalable green process for the synthesis of Calebin-A and its analogs.
The present invention fulfills the principle objective and provides further related advantages.